The present invention relates to a new composition for transdermal delivery of topically applied pharmaceutical preparations. The system comprises the use of the pharmaceutical agent and acidified nitrite contained within a delivery system to allow passage of both the specific pharmaceutical agent and nitric oxide to the skin.
The penetration of substances through the skin is important from both toxicological and therapeutic viewpoints. Passive delivery of most compounds across different epithelia is limited due to the excellent barrier properties afforded by these epithelia. The stratum corneum is the principal barrier to penetration of most chemicals. Conventional topical delivery systems are therefore restricted to either substances for local effects or to highly potent, small, lipophilic substances for systemic effects. It is also difficult to deliver ionic and high-molecular-weight drugs in therapeutically sufficient amounts by conventional systems.
By way of example, many medical and surgical procedures require topical anaesthesia. The use of local anesthetics requires an agent possessing the following general properties. It should not be irritating to the tissue to which it is applied, nor should it cause any permanent damage to nerve structure. Its systemic toxicity should be low because it is eventually absorbed from its site of administration. It is usually important that the time required for the onset of anaesthesia should be as short as possible. Furthermore, the action must last long enough to allow time for the contemplated medical or surgical intervention, yet not so long as to entail an extended period of recovery (J. Murdoch Ritchie & N. M. Greene Local Anaesthetics in Goodman & Gilman's: The Pharmacological Basis of Therapeutics, pages 311-331, McGraw-Hill Inc, (1992)).
Local anesthetics are rapidly absorbed into the circulation following topical administration to mucous membranes or denuded skin. It is extremely useful in achieving loss of sensation in a subject without the loss of consciousness, or the impairment of central control of vital functions. Typical uses, include minor invasive procedures such as venepuncture, e.g. for the collection of blood for diagnostic purposes from a patient, for the administration of therapeutic agents, whole blood or blood plasma to a patient, or prior to the administration of a general anaesthetic to a patient. However, it is a common feature among patients that the pain of injection can cause discomfort and in certain cases a patient, in particular juvenile subjects, can experience acute anxiety or panic brought on by the sight of a needle or of the injection itself. Such panic attacks can be characterised by fainting, vomiting or other related symptoms. Whether the adverse reaction is pain or a panic attack, the problem leads to poor patient compliance with advisable medical procedures. There exists a need therefore for improved local anaesthetic compositions that can overcome these problems.
Intact, healthy human skin presents an excellent natural barrier to the external environment and restricts the passive diffusion of pharmaceuticals. Local anaesthetics do not readily penetrate intact skin (McCafferty et al Br J Anaesth 60, pages 64-69 (1988)).
The insertion of a needle through the skin, for procedures such as phlebotomy or vaccination, is painful and may induce great fear and anxiety especially in children and the elderly. Painful experiences lead to reduced compliance, with heightened anticipatory anxiety and fear. The introduction of topically-applied cutaneous anaesthetic preparations such as EMLA™ (Eutectic Mixture of Local Anaesthetics) cream [Astra Pharmaceuticals Ltd.] (Arts et al Pediatrics 93, pages 797-801 (1994)) and more recently Ametop Gel™ [Smith & Nephew Healthcare Ltd.] (Freeman et al Paediatr Anaesth 3, pages 129-138 (1993)), represented a definite advance in clinical practice and are contributing to breaking the cycle of “needle phobia”.
Studies of the effects of these preparations have produced variable results (Molodecka et al Br J Anaesth 72, pages 174-176 (1994); Lawson et al Br J Anaesth 75, pages 282-285 (1995)). However, relatively slow onset times (EMLA™ 60-90 minutes; Ametop Gel™ 30-45 minutes) remain a deterrent to widespread clinical and patient acceptance with the need to organise clinic, ward and operating theatre routines accordingly. These methods are of no benefit in acute situations. Additionally, even following the manufacturer's recommendations for dosage and administration, potential exists for improvement in the degree of anaesthesia afforded by these treatments.
A percutaneous local anaesthetic with a more rapid onset time and increased potency would be helpful in organisational terms for emergency cases, community medicine and for an increasing number of paediatric medical and surgical day cases. Shortening of the period of anticipatory anxiety while achieving the maximal desensitising of the skin would clearly be clinically advantageous.
Nitric oxide [NO] is a potent vasodilator synthesised and released by vascular endothelial cells and plays an important role in regulating vascular local resistance and blood flow (Palmer et al Nature 327, pages 524-6 (1987)). In mammalian cells, NO is produced along with L-citrulline by the enzymatic oxidation of L-arginine. Nitric oxide is also involved in the inhibition of both platelet and leukocyte aggregation and adhesion, the inhibition of cell proliferation, the scavenging of superoxide radicals and the modulation of endothelial layer permeability. Nitric oxide also has been shown to possess anti-microbial properties, reviewed by F. C. Fang (1997) (J. Clin. Invest. 99 (12) 2818-2825 (1997)).
A potential therapeutic utility of the anti-microbial properties of NO is described in WO 95/22335. A pharmaceutical composition comprising nitrite in an inert carrier cream or ointment and salicylic acid was used to show killing of cultures containing E. coli and C. albicans. This activity was further tested against patients with fungal infection of the feet (“Athlete's Foot” or Tidea pedis) and showed that the condition was amenable to treatment with the acidified nitrite composition. However, the composition of nitrite and organic acid caused erythema (redness) of the skin.
In addition to internal cell-mediated production, NO is also continually released externally from the surface of the skin by a mechanism, which appears to be independent of NO synthase enzyme. Nitrate excreted in sweat is reduced to nitrite by an unknown mechanism, which may involve nitrite reductase enzymes, which are expressed by skin commensal bacteria. Alternatively mammalian nitrite reductase enzymes may be present in the skin which could reduce nitrite rapidly to NO on the skin surface (Weller et al J Invest Dermatol 107, pages 327-331 (1996)).
The production of NO from nitrite is believed to be through the following mechanism:NO2−+H+⇄HNO2  [1]2HNO2⇄N2O3+H2O  [2]N2O3⇄NO+NO2  [3]
Topical application of a sodium nitrite/ascorbic acid NO-generating system causes significant increases in skin blood flow in patients with Raynaud's disease and in normal healthy subjects without causing local irritation (Tucker et al Lancet 354(9191):1670-5 (1999); Harwick et al Clinical Science 100, pages 395-400 (2001)). The reaction can be terminated within a few seconds by gentle wiping of the skin with a tissue.